Gastrin-releasing peptide receptor (GPCR) mediates cell proliferation in the airway through its ligand, gastrin-releasing peptide (GRP), an important mitogen in the lung. Project 1 of the Lung Cancer SPORE will investigate the hypothesis that expression of GRPR in human airway cells is a predisposing risk factor for lung cancer. We further hypothesize that there is a sex difference in human GRPR expression, that may in part be responsible for sex differences in susceptibility in human GRPR expression, that may in part be responsible for sex differences in susceptibility to tobacco carcinogenesis.. Our preliminary data suggest GRPR expression is frequent in the airway cells of non-smoking and short-term smoking males. GRPR expression is also more frequent in cells cultured from long-term male smokers compared to male non- smokers and male short-term smokers. Preliminary evidence further suggests GRPR airway cell expression is found disproportionately in individuals with lung cancer. A corollary of our hypothesis is that GRPR expression may be modulated by both estrogens and nicotine. Estrogens may modulated GRPR expression through estrogen receptor beta expressed on lung fibroblasts and bronchial epithelial cells, while nicotine may modulate GRPR gene expression in the lung through nicotinic acetylcholine receptors on these cell types. We seek to obtain evidence for our hypotheses and its corollary by carrying out four Specific Aims: (1) demonstrate an increased frequency of expression of GRPR mRNA in the airway cells of individuals with elevated risk for lung cancer through a case-control population study to calculate sex- specific odds ratios for association of GRPR gene expression with a diagnosis of lung cancer; (2) quantify expression of GRP in different populations of cells found within airway biopsies of males and females without prior cell culture; (3) examine induction of GRPR expression in human lung fibroblasts and human bronchial epithelial cells from males and females by exposure to nicotine and estrogen, alone and in combination; and (4) examine expression of four other genes that may contribute to lung cancer risk in the same population as in Specific Aim One: gastrin releasing peptide (the ligand for GRPR), Estrogen Receptor alpha, Estrogen Receptor beta, and the GRPR-related gene, Neuromedin B receptor.